Malignant gliomas are resistant to natural killer cell immune surveillance. However, the mechanisms used by these cancers to suppress anti-tumor natural killer cell activity remain poorly understood. We have recently reported on a novel mechanism of innate immune evasion characterized by the overexpression of the carbohydrate-binding protein galectin-1 by both mouse and rat malignant glioma. Here, we investigate the cytokine profile of galectin-1-deficient GL26 cells and describe the process by which these tumors are targeted by the early innate immune system in RAG1-/- and C57BL/6J mice. Our data reveal that galectin-1 knockdown in GL26 cells heightens their inflammatory status leading to the rapid recruitment of Gr-1+/CD11b+ myeloid cells and NK1.1+ natural killer cells into the brain tumor microenvironment, culminating in tumor clearance. We show that immunodepletion of Gr-1+ myeloid cells in RAG1-/- mice permits the growth of galectin-1-deficient glioma despite the presence of natural killer cells, thus demonstrating an essential role for myeloid cells in the clearance of galectin-1-deficient glioma. Further characterization of tumor-infiltrating Gr-1+/CD11b+ cells reveals that these cells also express CCR2 and Ly-6C, markers consistent with inflammatory monocytes. Our results demonstrate that Gr-1+/CD11b+ myeloid cells, often referred to as myeloid-derived suppressor cells, are required for anti-tumor natural killer cell activity against galectin-1-deficient GL26 glioma. We conclude that glioma-derived galectin-1 represents an important factor in dictating the phenotypic behavior of monocytic Gr-1+/CD11b+ myeloid cells. Galectin-1 suppression may be a valuable treatment approach for clinical glioma by promoting their innate immune-mediated recognition and clearance through the concerted effort of innate myeloid and lymphoid cell lineages.